AMCP Format Dossier Requests: Manufacturer Response and Formulary Implications for One Large Health Plan

BACKGROUND: The Academy of Managed Care Pharmacy (AMCP) Format for Formulary Submissions, a template for health plans to use in developing formulary submission guidelines, has been widely adopted since its initial release in 2000. Many health plans request a dossier (a standardized set of clinical and economic evidence prepared by pharmaceutical manufacturers) to provide information for consideration during the formulary decision-making process. While dossier quality has reportedly improved over time, there is no recent research examining the response rate to dossier requests and the quality of dossiers received. OBJECTIVES: To perform an evaluation of pharmaceutical manufacturers' response to a request for a product dossier prepared using the AMCP Format, and to determine if dossier receipt was associated with a favorable formulary placement. METHODS: The pharmacy and therapeutics (P&T) committee of a mid-Atlantic health plan with approximately 3 million members reviewed 43 drug products from February 2004 through December 2005. A university-based clinical evaluation subcontractor requested dossiers in the AMCP Format by telephone and e-mail from the manufacturers' drug information center about 8 weeks before the committee meeting. A retrospective evaluation of the materials received from the manufacturers was performed. A logistic regression model was developed to determine if dossier receipt increased the likelihood of second-tier copayment formulary placement for new product reviews. RESULTS: Dossiers were requested for 43 products. We received dossiers for 25 products (58%), other drug information (e.g., journal reprints, product labeling) for 10 products (23%), a formulary kit for 4 products (9%), and no response for the remaining 4 products (9%). Of the 25 dossiers, 21 (84%) generally followed the AMCP Format. Unlocked interactive budget impact models were included in 5 dossiers (20%), and modeling reports (without an unlocked interactive model) were included in 12 dossiers (48%). Dossiers were more likely to be received when the time between U.S. Food and Drug Administration (FDA) approval and dossier request was 4 months (65% vs. 27% when less than 4 months; P less than 0.05) and when requested from a large manufacturer (top 25 in sales) compared with smaller manufacturers (75% vs. 43%; P less than 0.05). Dossier receipt did not improve a product's likelihood for preferred formulary placement; none of the new products for which dossiers were received were assigned to the second copayment tier compared with 33% of the new products with no supporting dossier. The logistic regression model failed to find any correlation between dossier receipt and preferred formulary placement. CONCLUSIONS: Manufacturers met the request for a dossier nearly three fifths of the time. The dossiers were of high quality and generally followed the AMCP Format; the models included in dossiers varied widely in their design and utility. The product manufacturer's size and the time between FDA approval and dossier request influenced the likelihood of dossier receipt. Receipt of a dossier did not appear to influence the likelihood of a product attaining preferred formulary status.

to dossier requests and the contents of dossiers received is lacking. The purpose of this study was to perform an evaluation of pharmaceutical manufacturers' responses to a request for a product dossier prepared using the AMCP Format for Formulary Submissions.
ss Methods The university-based unit of the authors (Advanced Concepts Institute [ACI] of the University of the Sciences in Philadelphia) was contracted by a health plan to develop and present detailed product reviews (written and oral presentations) to their P&T committee in 2004 and 2005. This multistate health plan is located in the mid-Atlantic region of the United States, provides medical and pharmacy benefit coverage for approximately 3 million members, and offers a pharmacy benefit with a 3-tier copayment design. The health plan' s P&T committee meets semimonthly to conduct both new product reviews and class reviews.
To support the development of the detailed product reviews, ACI requested AMCP Format dossiers by telephone or e-mail from the product manufacturers' drug information center about 8 weeks before the committee meeting. If notified that a dossier was not available, ACI requested other drug information materials to support monograph development. If no materials were received within 4 weeks of the committee meeting, a follow-up request for a dossier or other drug information was made. The P&T committee did not delay a product review if materials were not received from the manufacturer; in such instances, a detailed product review was prepared using information obtained by ACI through other sources.
A retrospective analysis of the manufacturers' responses to the dossier request was performed. All materials received during the 6-week period starting on the initial dossier request date and ending 2 weeks before the P&T committee meeting (the submission date of review materials to the health plan) were catalogued. The materials were classified into 1 of 3 categories: (1) dossier (materials titled or identified as such; or materials not titled or identified as a dossier that clearly followed the AMCP Format or another submission format); (2) formulary kit (materials titled or identified as such); or (3) other drug information (including product labeling, reprints of key publications, meeting abstracts and posters, and economic analyses  Checklist, and Model. If included in the dossier, the pharmacoeconomic or disease impact-model was classified as a working model (a spreadsheet or other model allowing for baseline variable manipulation and calculation review) or a model report (the results of a model were presented, but a working model was not included). Lastly, the reviewer' s subjective determination on whether the dossier followed the AMCP Format was recorded; dossiers exhibiting general accordance with the Format's prescribed layout and content without any evidence of omission of requested information were considered to have followed the AMCP Format.
For comparison purposes, dossier requests were classified as new product reviews (requested to aid a committee review of a recently approved single product) or a class review (requested to aid a committee review of all the products within the class). For each dossier request, the request lag time (equal to the time difference between the U.S. Food and Drug Administration [FDA] approval date of each agent and the date of the dossier request) was calculated, and the size of the product manufacturer (based on the preceding year' s sales data) 11,12 was determined. The FDA chemical type and review classification of all products were also noted.
Tests of significance were performed on continuous and categorical data (t test and chi-square, respectively) to determine if any statistically significant differences existed between groups (new product reviews vs. class reviews, and groupings for manufacturer size, dossier request lag time, and FDA chemical type/review classification). Following the P&T committee review, the committee' s decision on the product' s formulary placement was noted. All new products received a full formulary review. For new product reviews, a logistic regression model was developed to determine if dossier receipt was associated with a favorable (second-tier copayment) formulary placement. In addition to dossier receipt, variables accounted for in the regression model included (at the time of formulary review) manufacturer size, number of competing in-class agents, number of competing in-class agents on formulary, presence of in-class generic formulary agents, and cost comparison (average wholesale price) to competing in-class formulary agents.

ss Results
The P&T committee selected 43 drug products for review at 10 committee meetings occurring during the evaluation period (a mean number of 4.3 [±3.8] per committee meeting; range: 2-13). The characteristics of these products are reviewed in Table 1. A majority of the products (72%) were new product reviews. Eight therapeutic areas were covered by dossier requests; products in the cardiovascular and central nervous system therapeutic areas were most commonly requested. The mean length of time between FDA product approval and the dossier request was 5.2 ± 2.9 months for products covered by new product reviews and 9.0 ± 4.4 years for products cov-ered by class reviews. Thirty-seven percent of all dossier requests went to the 10 largest pharmaceutical manufacturers (by U.S. sales figures), and more than half of all requests went to the top 25 manufacturers. Fifty-eight percent of the products were classified by the FDA as new molecular entities, followed by new formulation (21%) and new combination (14%); a majority of the products (84%) underwent a standard FDA review.
The manufacturer response to an AMCP Format dossier request is presented in Figure 1. Of the 43 products for which dossiers were requested, dossiers were received for 25 (58%). Formulary kits were sent in response to a dossier request for 4 products (9%), other drug information was sent for 10 products (23%), and no response was obtained from the manufacturers of the remaining 4 products (9%).
Dossiers were more likely to be received when the lag time between FDA approval and dossier request was ≥4 months (65% [13/20] when ≥4 months vs. 27% when <4 months; P <0.05) ( Table 2). The receipt of dossiers tended to be higher when requested for products covered by class reviews (75%) than those for new product reviews (52%), although this difference did not achieve statistical significance. The size of the manufacturer of the requested product played a role in dossier receipt; receipt of dossiers was more likely when requested from a larger manufacturer than from a smaller one (75% for top 25 manufacturers vs. 43% for all others; P <0.05). Dossier receipt was also more likely for new molecular entities compared with new formulations (76% vs. 22%; P <0.01). The size of the dossiers received ranged from 39 to 210 pages of content, excluding clinical trial reprints. The majority of the dossiers that were received (84%) were judged by the authors to have generally followed the AMCP Format. Three of the 4 dossiers that were judged to have not followed the AMCP Format excluded numerous studies (with positive and negative results) from the dossier, while the fourth failed to provide succinct study summaries for the key clinical studies. None of the dossiers followed any other recognized dossier format such as the Regence BlueShield or Ontario guidelines. Dossier sections that were included or addressed in less than 70% of submissions were (1) a pharmacoeconomic or disease manage-ment impact model (included in 68% [48% + 20%] of dossiers), (2) reprints of all key trials (68%), (3) summaries of outcomes studies and economic evaluation supporting data (64%), (4) a review of clinical and disease management intervention strategies (40%), and (5) the formulary submission checklist (0%) ( Table 3). There were no statistically significant differences between new product reviews and class reviews with regard to likelihood of inclusion in any one section of a dossier. Additional information (information not requested in the AMCP Format) was included in 36% of the dossiers; executive summaries, and a section titled "answers to frequently asked questions" accounted for most of the additional content.
Pharmacoeconomic or disease-impact models were included in 17 of the 25 dossiers received. Of these, only 5 (20% of all dossiers, 29% of all dossiers with models) included unlocked interactive economic or budget-impact models in which the user could alter key variables and enter health plan-specific data. All 5 of these models were budget-impact models. The remaining 12 models (48% of all dossiers, 71% of all dossiers with models) provided only reports describing the economic analyses performed in varying length and detail.
Overall, products evaluated as part of a new product review were assigned preferred formulary placement (second copayment tier) 16.1% (5/31) of the time. Receipt of a product dossier to support the development of the detailed product review did not improve a product' s likelihood for preferred formulary placement; none of the 16 new product reviews for which dossiers were received were assigned to the second copayment tier of the formulary, compared with 5 of the 15 new product reviews (33%) for which dossiers were not received. The logistic regression model failed to find any correlation, positive or negative, between dossier receipt and preferred formulary placement for new product reviews.

ss Discussion
In October 2006, the AMCP executive director announced that the Academy would begin the process of evaluating the utility of dossiers in the formulary decision process. 13 While a few studies have evaluated the quality of responses received in response to a dossier request, 10,14 to our knowledge there have been no publications describing the response rate to dossier requests and no evaluations about how dossiers might affect the formulary decision-making process. While we do not know the methodology or extent to which this forthcoming research will address those questions, our analysis represents the first attempt at answering some of these important questions.
In this analysis, manufacturers supplied a dossier in response to a request for an AMCP Format dossier 58% of the time. This percentage is lower than anticipated, especially given the large-scale adoption of the AMCP Format by health care management organizations. 6,15 While some manufacturers stated that they believed dossier production inflicted a great expense on their organization, 16,17 no recent complaints have been noted. As evidence suggests that adoption of a systematic formulary review process may lead to an increase in pharmaceutical spending in health programs, 18 manufacturers should strive to develop dossiers for those organizations that have adopted such evidence-based formulary reviews.

Dossiers Received, Stratified by Review Type, Manufacturer Size, FDA Chemical Type/Review Classification, and Time between FDA Approval and Dossier Request
Factors that influenced the likelihood of dossier receipt included the length of time between FDA approval and the dossier request, and product manufacturer size. A period of at least 4 months between FDA approval of a product and request of a dossier increased the likelihood of dossier receipt by 140% for new product reviews. The AMCP Format recommends that manufacturers should have dossiers completed by the time of the product launch to avoid any delays in responding to unsolicited dossier requests; 4 our findings indicate that many manufacturers may not be meeting this recommendation. The higher likelihood of dossier receipt for products covered by class reviews (75%) over new product reviews (52%) may be a result of the difference in lag time between the 2 types of reviews. Large manufacturers (top 25 in sales) were able to meet requests for dossiers more frequently (75%) than were small manufacturers (43%); this difference remained once the dossier requests with a lag time <4 months were eliminated ( "Other drug information" and formulary kits were received in response to 33% of requests. While formulary kits have essentially been replaced by dossiers as the information package of choice for health care decision makers, manufacturers continue to produce and distribute them. Several manufacturers offered to provide them in addition to the dossier if we so desired. However, we did not receive any formulary kits that were labeled as dossiers, an experience described by others. 19 Despite repeated attempts, no response of any kind was received in response to 9% of the requests. We found this result surprising; at the very least a minimal response (such as study reprints) should have been received. Notably, all 4 of the "no responses" came from smaller manufacturers.
The majority of the dossiers that were received generally followed the AMCP Format. Three of the 4 dossiers that did not follow the AMCP Format failed to include summaries of all the trials that included the product. While we judged some dossiers to have followed the AMCP Format even if they had failed to include 1 or 2 studies in the spreadsheet of all clinical/ outcomes/economic studies, these 3 dossiers were missing a large number of trials from their spreadsheets, and 2 of the 3 dossiers appeared to include only those trials that provided www.amcp.org Vol. 13 14 Products evaluated as a new product review received preferred formulary placement 16.1% of the time. By itself, receipt of a dossier did not influence the formulary decision. Our finding that none of the products with dossiers received preferred formulary status was far less than the 54% reported by Fullerton and Atherly for another health plan, 9 although the requirements for formulary acceptance and level of formulary placement were not clearly delineated in their report. Our results are also inconsistent with the recent case report from Watkins et al. 20 Nevertheless, in the current study, products for which dossiers were received fared worse than those products for which dossiers were not received, as 33% of those products without dossiers were assigned preferred formulary status. While we would not suggest that submission of a dossier actually lessens a product' s chances for preferred formulary placement, it is clear that preparation of a dossier provides no guarantee that a product will be looked on favorably by a P&T committee. A logistic regression model accounting for several other factors that influence formulary decision making failed to find any correlation between dossier receipt and preferred formulary product placement.

Limitations
While the logistic regression model employed in the current study accounted for many factors that could potentially influence formulary placement (e.g., number of competing in-class agents, number of competing in-class agents on formulary, presence of in-class generic formulary agents, and cost comparison (average wholesale price) to competing in-class formulary agents), 2 of the most significant variables that influence formulary decision making, the safety and efficacy of the product, were not included in the model. To do so would have required development of comparative measures for safety and efficacy that would have to be validated and would certainly generate considerable controversy. Nonetheless, we believe that this model represents a useful first step in analyzing the influence of dossiers in the formulary decision-making process.
In addition to the limitations in the logistic regression model, several other limitations in our analysis merit mention. First, a change in the AMCP Format criteria occurred with the release of Format version 2.1 in April 2005. 4 While Format version 2.1 requested some additional information to be supplied in dossiers, all the information requested in Format version 2.0 was carried over into the new version (albeit streamlined in places). As such, a quantitative evaluation using the Format version 2.0 criteria for dossiers received throughout the entire evaluation period is acceptable because it did not result in any differences in evaluating the dossiers received throughout the analysis period.
Second, one manufacturer of a single product under review claimed to have a product dossier but refused to send it to us, stating it would only send a dossier to the health plan directly. Since we were prohibited from revealing the identity of the health plan we were working with, we had to accept the manufacturer' s offer to send "other drug information" (product labeling and study reprints) in place of the dossier. While the possibility exists that other manufacturers did not send dossiers because (1) we were not a health plan and (2) we did not identify the health plan we were working with, no other manufacturer explicitly stated that these factors would prevent us from receiving a dossier.
Third, we utilized the FDA approval date as one benchmark for assessing the likelihood of dossier receipt. The product launch date may be a better index for dossier availability than the FDA approval date since not all FDA-approved products have been launched by their manufacturer. Three of the products under evaluation in this study had received FDA approval but had not been launched by their manufacturer prior to the date of the initial dossier request. However, this did not affect our findings, as removal of these 3 products from the analysis did not alter the statistical significance of any of the results.

ss Conclusions
In summary, manufacturers provided a dossier in response to a specific request for an AMCP Format dossier nearly 60% of the time. These dossiers generally followed the AMCP Format and addressed most of the information requested in the Format. While the models included in dossiers varied widely, most were not unlocked interactive economic or budget-impact models that allowed the user to alter key variables and enter health plan-specific data, thereby limiting the model' s utility. Factors such as the size of the manufacturer of the product and the length of time between the product' s FDA approval date and the dossier request can predict the likelihood of receiving a dossier. While we did not find that the receipt of a dossier improved a product' s likelihood for preferred formulary placement, manufacturers should continue to provide dossiers in response to unsolicited requests for product information. Additional research in this field can help further determine the influence that dossiers play in the formulary decision-making process.